Aims: We are carrying out a population-based case-control study of facial clefts in Norway, where the rate of cleft lip and palate is one of the highest in the world. This study, which began in 1996 and will run through 2002, attempts to enroll all babies born in Norway with a cleft lip or palate. Mothers provide detailed information on occupational and other exposures to potentially toxic substances, as well as nutrition, personal habits and medical history. Control infants are selected randomly from all live births. In order to investigate possible genetic susceptibility to teratogens, biological samples (blood or cheek swabs) are collected from cases, controls, and their biological parents. When completed, this will be one of the largest and most comprehensive studies of this common birth defect ever conducted. Procedures and techniques: This population-based case-control study of facial clefts is being carried out in Norway, which has one of the highest reported prevalences of cleft lip in the world. Furthermore, the organization of health services and medical records in Norway offers an efficient setting for careful epidemiologic studies. All Norwegian infants with facial clefts receive their care (at Government expense) from one of two major hospitals. Clinicians from these two hospitals are collaborators in this project. We identify cases within the first week of birth, and select controls randomly from all live births born in Norway. Mothers of cases and controls fill out a self-administered questionnaire at about three months after birth, including a nutritional survey developed and validated for Norwegian subjects. The questionnaire includes detailed occupational exposure questions provided by a Norwegian industrial hygienist, and questions on household and recreational exposures. Blood for DNA analysis are collected from cases and their two parents. Cheek swabs are also collected from the parents and siblings of cases, and from controls, their parents and siblings. Infant blood samples routinely collected for PKU testing are retrieved for cases and controls. These redundant collections of biological samples will provide a resource for extensive exploration of candidate genes. Accomplishments: Since the start of the study in May 1996, 550 babies with registered facial clefts have been born in Norway. 90% of their mothers have agreed to participate in our study. A random sampling of birth records starting September 1996 has identified 806 surviving live births as controls. 82% of their mothers have enrolled. PKU blood samples are in hand for 93% of enrolled cases and 97% of enrolled controls. Blood samples were drawn at surgery from 86% of cases and 87% of case mothers; 75% of case fathers have provided blood samples drawn by their own physician. Buccal swabs have been collected from 79% of the controls and their families. We expect to complete the enrollment of controls in August 2001 and the enrollment of cases in October 2001. We estimate a final sample size of 600 cases and 800 controls. The availability of genetic samples from these clefts cases and their biological parents led me to consider the tools available for analyzing case-parent triad data. The best-known procedure is the "transmission disequilibrium test" (or TDT). This test has the limitation of being unable to detect associations between a maternal allele and the risk of disease in her offspring. This is a considerable limitation in birth defects epidemiology, since it is plausible that a particular alleleic variant of the mother could affect her fetus' intrauterine exposure to a teratogen (for example by influencing maternal metabolism). While we would be able detect such effects in our clefts study using the control mothers, I realized that we should also be able to do so within the case-parent triads alone. Any maternal allele that increases fetal risk of clefting would be more common among case-mothers than among case-fathers, given a few simple assumptions (Wilcox et al. Amer J Epidemiol 1998). Building on this insight, Clarice Weinberg has developed an elegant analytic structure for estimating the risk of offspring disease with a given parental allele, using only cases and their parents. This has proved to be a versatile and powerful method, in many respects superior to the TDT (Weinberg et al., Amer J Hum Genet 1998). We have begun a preliminary genetic analysis of the TGF-alpha allele and the MTHFR allele among 225 cases and their parents, which will allow us to use our statistical method on real data.